Hiwa K. Saaed PhD
Pharmacology & Toxicology
College of Pharmacy
University of Sulaimani
Ref, Lippincott's Illustrated Reviews of Pharmacology 5th ed 2012
Analgesic – an agent that selectively relieves pain by
acting in the CNS or on peripheral pain mechanisms, without
significantly altering the consciousness
acute or chronic
Consequence of complex neurochemical processes
Subjective: perceptive and descriptive
Alleviation of pain depend on its type”
• Headache, arthritic pain Rx NSAIDs
• Neurogenic pain Rx TCA Amitriptyline or SSRI Fluoxetine
• Severe or chronic malignant pain Rx Opiods are DOC
History / Definitions
• Ancient Egypt papyrus records reported the use of opium for pain
• Opium– mixture of alkaloids from the poppy seed
• Opiates ‐ naturally occurring alkaloids such as morphine or
codeine obtained from the juice of the opium poppy
• Opioid – broad term to describe all “natural or synthetic ”
compounds that work at the opioid receptors and produce
endogenous opioid peptide neurotransmitters
endorphin, enkephalins & dynorphins
Opiods act by binding to specific opioid receptors in the CNS to produce the
action of endogenous peptide neurotransmitters
Mu(μ), Kappa(κ), Delta (δ)
Opioids interact with receptors on the membranes of certain
cells in the CNS, on nerve terminals in the periphery on cells of
the gastrointestinal tract and the anatomic regions urinary
Analgesic properties are mediated:
• mainly via μ receptors
• and κ receptors of the dorsal horn of the spinal cord.
• Enkephalins interact more selectively with the δ receptors
in the periphery.
Endogenous opioid receptors
Decrease GIT motility
analgesia (spinal & supraspinal)
release of growth hormone
Present in limbic system
Hallucination (both visual &
Respiratory and vasomotor
#“less specific” bind with non opioid
agent e.g hallucinogen
Mechanism of Action
All are G-protein coupled receptors and
inhibit adenylate cyclase.
They are also involved in
• postsynaptic hyperpolarization
(increasing K+ efflux)
• or reducing presynaptic Ca++ influx;
thus inhibits neuronal activity.
High densities of opioid receptors on peripheral nerve
fibers, immune cells and five general areas of the CNS:
1. Brainstem: respiration, cough, nausea &
vomiting, BP, papillary diameter and stomach secretion.
2. Medial thalamus: mediating poorly localized deep pain
3. Spinal cord: in the substantia gelatinosa are involved in
the receipt & integration on sensory input leading to the
attenuation of painful afferent stimuli.
4. Hypothalamus: neuroendocrine secretion.
5. Limbic system: the greatest concentration in the
amygdale, a major role in emotional behavior &
response and little analgesic effect.
6. Periphery: they inhibit Ca+2 dependent release of
excitatory, pro-inflammatory substances (substance P)
7. Immune cells: undetermined.
• The strongest naturally occurring analgesic drugs are found in
opium from the poppy flower,
• morphine and less potent codeine.
• These drugs show a high affinity for the μ receptor and less
affinity for the κ and δ receptors.
• Exert its effects through interaction with central & peripheral
opioid receptors, binding results in hyperpolarization, inhibition
of nerve firing and presynaptic inhibition of transmitter release
• Acts at the κ receptors in lamina I & II of the substantia gelatinosa
of the cord and decreases the release of substance P,
• it also inhibits the release of excitatory transmitters from
nociceptive nerve terminals centrally and in the cord
Morphine‐Pharmacological ActionsAnalgesia: Opioids cause pain relief by both
• raising the pain threshold at the spinal cord level
• altering the central perception of pain; awareness of pain
remains but it loses its unpleasant character
• Opioids produce a sense of contentment and well being, this
may be related to stimulation of the ventral tegmental tract
• Opioids cause respiratory depression by decreasing the
sensitivity of central respiratory neurons to CO2
• Occurs at therapeutic doses and as dose increases respiratory
arrest will occur
nsSuppression of cough reflex:
• Antitussive properties do not correlate with analgesic or respiratory
depression effects; this appears mediated via a different receptor complex
• Results from stimulation of μ and κ receptors located in the
Edinger‐Westphal nucleus of CN III,
• resistant to tolerance,
‐ Pharmacological ActionsEmesis:
• Opioids directly stimulate the chemoreceptor trigger zone in the area
postrema that causes vomiting
• Opioids relieve diarrhea by decreasing gut motility and increasing the
tone of intestinal smooth muscle
• Constipation is also resistant to tolerance
• Biliary spasm is exacerbated by increasing biliary tone with sphincter of
• At large doses morphine produces hypotension & bradycardia
‐Pharmacological ActionsHistamine release:
• Morphine causes mast cell degranulation, the release of histamine
causing urticaria, itching, diaphoresis and vasodilation
• In asthmatics it may precipitate bronchospasm
• inhibits the release of GnRH, CRH
• and deceases the release of LH, FSH & ACTH and β‐endorphin
• Decrease levels f Testosterone and cortisol
• Increase Prolactin and GH release via suppression of dopamine levels
• Increase ADH release
‐ Therapeutic Uses ‐
• Few drugs are as effective as morphine for the relief of pain
• Treatment of Diarrhea
• codeine and dextromethorphanare congeners with greater antitussive effects
• Acute Pulmonary Edema:
• – IV morphine dramatically relieves the dyspnea associated with pulmonary
edema due to LV failure
‐ Pharmacokinetics ‐
• Morphine is poorly absorbed orally; codeine is a much more effective oral
• Both undergo extensive first pass metabolism in the liver. Inhalation is an effective
route but has found favor only with non‐medicinal administration
• Implantable morphine pumps are also now use for chronic pain
• Morphine readily enters all body tissues except the brain; morphine is the least
lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS
much more quickly)
‐ Pharmacokinetics ‐
Conjugated in the liver,
morphine–6‐glucuronide is a much more potent analgesic;
however morphine‐3‐glucuronide is less analgesic
Both are excreted in the urine
with small amounts excreted in the bile
Hepatic & renal dysfunction both prolong the normal 4‐6 hour duration of action
when administered systemically to morphine-naive individuals
• but considerably longer when injected epidurally, because its low lipophilicity
prevents redistribution from the epidural space.
‐ Pharmacokinetics ‐
• Note: A patient's age can influence the response to morphine.
• Elderly patients are more sensitive to the analgesic effects of the
drug, possibly due to decreased metabolism or other factors, such as
decreased lean body mass, renal function, etc. They should be
treated with lower doses.
• Neonates should not receive morphine because of their low
‐ Adverse Effects ‐
• Severe respiratory depression (μ, δ and κ receptors)
• Constipation (variable, μ and κ receptors)
• Nausea and vomiting
• Pupillary constriction (μ/κ receptors)
• Caution must be exercised when opiates are used in those with liver
or renal failure
• Allergy enhanced hypotensive effects
• Elevation of intracranial pressure particularly head injury
• Enhance cerebral and spinal ischemia
‐ Adverse Effects ‐
• In BPH, morphine cause acute urinary retension
• Patients with adrenal insufficiency or myxedema may experience
extended and increased effects from the opioids. Morphine should
be used with cautiously in patients with bronchial asthma or liver
• Note: Many of the effects above can be inhibited by opioid receptor
antagonists such as naloxone.
• Rapid development of tolerance
• Physical dependence and abstinence syndrome
‐Tolerance & Physical Depe
• Repeated use produces tolerance to the effects of respiratory
depression, analgesia, euphoria and sedation
• Tolerance does not develop to miosis and constipation
• Physical & psychological dependence readily occurs
• Withdrawal induces a syndrome associated with autonomic, motor
and psychological responses that are incapacitating, rarely are these
comparison of the maximum Efficacy versus
Addiction / Abuse Potential of Various Opioids
• Detoxification of heroin- or morphinedependent individuals is usually
accomplished through the oral
• buprenorphine, or
• The depressant actions of morphine are enhanced by
phenothiazines, MAOIs, and TCAs.
• The analgesia inexplicably enhanced by Low doses of amphetamine
Meperidine “Pethidine” (μ,…κ)
• A synthetic opioid structurally unrelated to morphine
• It binds to μ receptors with some binding at κ receptors
• Causes respiratory depression similar to morphine, but less urine retention
• no significant CV effect when given orally.
• IV administration produces a decrease in PVR resulting in increased peripheral
blood flow & HR.
• pupillary dilation via an atropine –like effect.
• Therapeutic uses:
Severe acute pain
Lacks antitussive activity
No anti diarrhea;
Obstetrics; Produces less smooth muscle contraction/ spasm than morphine
• Well absorbed form the GI tract; it is most often given IM
• Shorter duration of action than morphine (2‐4 hours)
• Demethylated to normeperidine in the liver and excreted in the urine
NB. Because of shorter action and different route of metabolism, meperidine is
preferred over morphine during labor
With large repeated doses normeperidine (demethylated meperidine)
• anxiety, muscle tremors and convulsions
• Causes papillary dilation (vs. miosis with morphine) in large doses
• Hyperactive reflexes
• Severe hypotension when admin. postop.
• +neuroleptics: enhanced depression
• +MAOI: severe reactions convulsion & hyperthermia
• Cross‐tolerance with other opioids
• This is a synthetic orally effective opioid that
• is equipotent to morphine
• but induces less euphoria
• has a longer duration of action
• Mechanism of action:
• Binds to the μ receptor.
• An equipotent analgesic to morphine
• Causes miosis, respiratory depression, biliary spasm and constipation just like
• Therapeutic uses:
• Used for controlled withdrawal from heroin & morphine
• Self addictive but the withdrawal syndrome is somewhat milder but more
protracted than with other opioids
• Readily absorbed orally, t1/2 24hrs
• Highly protein bound so remains in tissues for a prolonged period.
• Transformed in the liver and excreted by the urine as mostly inactive metabolites
• Adverse effects:
• Similar to morphine particularly the risk of addiction
• Chemically related to meperidine but miosis
• has 100 times the analgesic potency of morphine; used in anesthesia and
as analgesia postop & during labor
• Highly lipophilic: elimination half‐life is longer than morphine’s as
• Rapid onset of action and a short duration (15‐30 minutes)
• Can be used IV, epidurally or intrathecally. Transmucosal and transdermal
preparations are available
• Metabolized to an inactive metabolite by the cytochrome P4503A4
system. Drug metabolites are eliminated through the urine.
• Like morphine fentanyl causes miosis (vs. mydriasis)
• Particular risk of the transmucosal or transdermal routes is
respiratory depression; these delivery routes create a reservoir of
drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and
the offset is prolonged
• Fentanyl is often used during cardiac surgery because of its negligible
effects on myocardial contractility.
• Muscular rigidity, primarily of the abdomen and chest wall, is often
observed with fentanyl use in anesthesia.
• Adverse effects of fentanyl are similar to those of other µ-receptor
• Because of life-threatening hypoventilation, the fentanyl patch is
contraindicated in the management of acute and postoperative pain or
pain that can be ameliorated with other analgesics.
• Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in
their potency and metabolic disposition.
• Only Sufentanil is even more potent than fentanyl others are less potent
• Heroin is produced by the diacetylation of morphine which results in a
three fold increase in its potency
• Acetylation allows it to cross the BBB much more rapidly yielding a more
• May be used IV or smoked, both allow for rapid distribution,
• heroin is metabolized to morphine
• No medical indication for its use in the clinic.
• is a semisynthetic derivative of morphine.
• It is orally active and is sometimes formulated with aspirin or
• It is used to treat moderate to severe pain and has many properties in
common with morphine.
• Oxycodone is metabolized to products with lower analgesic activity.
• Excretion is via the kidney.
• Abuse of the sustained-release preparation (ingestion of crushed tablets)
has been implicated in many deaths.
• It is important that the higher-dosage forms of the latter preparation be
used only by patients who are tolerant to opioids.
• Converted to morphine thus:
• Much less analgesic than morphine
• Less euphoria and has much lower abuse potential and rarely produces
• An effective oral analgesic
• Does possess significant anti‐tussive effects at sub‐analgesic doses
• Often formulated with either acetaminophen, aspirin of ibuprofen; care
but be exerted when these are used with over the counter analgesic to
avoid overdose with the non‐opioid agent
• A synthetic congener of codeine dextromethorphan lacks analgesic
properties is an effective anti‐tussive available without prescription
• Derivative of methadone,
• dextro isomer is analgesic, levo isomer is antitussive
• Used for mild to moderate pain; its opioid dose equipotency is
about half of codeine (require twice dose)
• Often formulated with another over‐the‐counter analgesic;
combination has greater effect than either drug alone
• Toxic doses may produce cardio and pulmonary toxicity particularly
when taken in combination with alcohol and/or sedatives in
addition to CNS depression
• Opioid antagonists can reverse the pulmonary and CNS effects but
not the cardiotoxicity
& Partial Agonists
Drugs that stimulate one receptor but block another
Effects of these drugs depend on previous exposure to opioids
Naïve patients – drugs act as agonists; produce pain relief
Opioid dependent patients – drugs show blocking affects; withdrawal
• Pentazocine acts as an agonist on k receptors and is a weak antagonist at
µ and delta receptors.
• Pentazocine promotes analgesia by activating receptors in the spinal
cord, and it is used to relieve moderate pain.
• It may be administered either orally or parenterally.
• Pentazocine produces less euphoria compared to morphine.
• In higher doses, the drug causes respiratory depression and decreases the
activity of the gastrointestinal tract.
• High doses increase blood pressure and can cause
hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The
latter properties have led to its decreased use.
• In angina, pentazocine increases the mean aortic pressure and
pulmonary arterial pressure and, thus, increases the work of the heart.
• The drug decreases renal plasma flow.
• Despite its antagonist action, pentazocine does not antagonize the
respiratory depression of morphine,
• but it can precipitate a withdrawal syndrome in a morphine abuser.
Tolerance and dependence develop on repeated use.
Mixed Agonists‐Antagonists & Partial
• A partial agonist at μ receptors producing morphine‐like effects in
naïve users but precipitating withdrawal in morphine dependents
• Metabolized in the liver and excreted in the urine and bile
• May be taken sublingually or parenteral and possess a long duration
• Adverse effects respiratory depression not reversible by
naloxone, hypotension and nausea
• Main use is in opioid detoxification as its withdrawal syndrome appears
less severe and of shorter duration than methadone
• Available outside of the specialized clinic allowed to dispense
methadone for opiate withdrawal
• Bind with high affinity to the μ, κ & δ receptors but fail to activate the
• In normal individuals, these agents produce no effect but in those with
opiates present, they induce an acute withdrawal syndrome
• Reverses the coma and respiratory depression associated with opioid
• IV administration produces a reversal of respiratory depression within
• Binding affinity is 10X greater at the μ receptor than κ
• Relatively short T1/2 (60‐100 minutes) so reversal will often abate
requiring repeat administration
• Similar actions as naloxone but an oral agent with a much longer
duration of action
• Single dose able to antagonize the effects of heroin for up to 48 hours
• is a parenteral opioid antagonist with actions similar to that of naloxone
• It can be administered IV, intramuscularly, or subcutaneously.
• Its half-life of 8 to10 hours is significantly longer than that of naloxone
and several opioid agonists.